FRAMINGHAM, Mass.–(BUSINESS WIRE)–Alzheon, Inc., a clinical-stage biopharmaceutical company focused on developing new medicines for patients suffering from Alzheimer’s disease (AD) and other neurodegenerative disorders, today announced the discovery of an endogenous substance in human brain that inhibits the formation of neurotoxic beta amyloid (Aβ) oligomers, which are key drivers of AD pathogenesis. The substance was identified as 3-sulfopropanoic acid (3-SPA), the primary metabolite of tramiprosate and of its prodrug ALZ-801 in humans. The cognitive improvements observed in AD patients in the tramiprosate Phase 3 studies1,2 may be attributed, in part, to the therapeutic effects of 3-SPA in the brain. This discovery indicates a potential protective role of 3-SPA in aging human brains and in AD, and elucidates the beneficial pharmaceutical attributes of ALZ-801, including a favorable safety profile, selectivity against Aβ oligomers, and excellent brain penetration.3

In this new study, Alzheon scientists expanded on the previous finding that tramiprosate and its prodrug ALZ-801 are consistently metabolized in humans to a single major metabolite, 3-SPA. The new analyses found that 3-SPA inhibits the formation of toxic soluble Aβ oligomers, comparable to the recently described effects of tramiprosate.4 In evaluations of non-treated and treated AD patients, Alzheon scientists showed that the levels of 3-SPA were up to 12 times greater in AD patients who received oral tramiprosate, than in drug-naïve or placebo-treated patients. These data further elucidate the mechanism of action supporting the development of Alzheon’s Phase 3-ready candidate ALZ-801, an optimized prodrug of tramiprosate, with a substantially improved pharmacokinetic and safety/tolerability profile compared to tramiprosate.3

The presence of an endogenous substance that can prevent Aβ oligomer formation also suggests the possibility of a protective endogenous anti-Aβ oligomer pathway (“Aβ oligomer brake pathway”) within the human central nervous system, with the potential to prevent or delay the onset of AD. Such physiological anti-Aβ oligomer pathway could modulate the neurotoxic effects of abnormal Aβ aggregation in the aging human brain.

“We are excited to contribute to a better understanding of the pathogenic and therapeutic mechanisms in Alzheimer’s disease. The results from this publication suggest a potential protective role of endogenous 3-SPA in normal human brains, guarding against the formation of beta amyloid oligomers that cause neurodegenerative disorders such as Alzheimer’s,” said Martin Tolar, MD, PhD, Founder, President and CEO of Alzheon. “In addition, our results suggest a potential contribution of 3-SPA to the clinical efficacy of ALZ-801 and connect it more closely to the protective effects against neurotoxic amyloid oligomers. While targeting soluble amyloid aggregates is the only therapeutic approach to date that has shown a disease modifying effect in Alzheimer’s patients, no drugs have been approved yet that can slow or stop the disease. This new discovery and mechanistic data strongly support our therapeutic approach and strengthen Alzheon’s commitment to confirm the efficacy of ALZ-801 in APOE4 carriers, a genetically-defined subset of Alzheimer’s patients.”

The study entitled “Discovery and Identification of An Endogenous Metabolite of Tramiprosate and its Prodrug ALZ-801 that Inhibits Beta Amyloid Oligomer Formation in Human Brain,” appeared in the most recent issue of the peer-reviewed publication CNS Drugs, and is available through open access https://link.springer.com/article/10.1007/s40263-018-0554-0. Key findings of the study include the following:

In drug-naïve elderly patients with memory deficits due to a variety of neurodegenerative diseases, 3-SPA was present endogenously in cerebrospinal fluid and plasma samples, suggesting that this substance may be a physiological protective mechanism in aging brain that counteracts amyloid aggregation leading to AD.

Using advanced molecular methodologies, the scientists showed that 3-SPA specifically inhibits aggregation of Aβ oligomers, thereby confirming the potential role of this endogenous substance in the anti-Aβ oligomer mechanism of action of tramiprosate and ALZ-801.

In AD patients who received a 150 mg twice-daily dose of oral tramiprosate, Alzheon found that the levels of 3-SPA in cerebrospinal fluid were up to 12 times greater than in drug-naïve or placebo-treated patients. Clinical improvements observed in AD patients who received tramiprosate in Phase 3 studies,1,2 may be partially explained by the therapeutic effects of the metabolite in the brains of these patients.

Consistent with the favorable clinical and preclinical safety profile of oral ALZ-801 and its parent molecule tramiprosate,1,2,3 their major metabolite, 3-SPA, is also well tolerated, as expected since 3-SPA is an endogenous substance.

This research builds on the previous discovery by Alzheon scientists of the molecular mechanism of action of tramiprosate to inhibit Aβ monomer aggregation and formation of toxic Aβ oligomers through an ‘enveloping’ of the amyloid peptide that prevents misfolding into soluble amyloid aggregates.3

“Our published findings suggest that an endogenous substance, 3-SPA, may protect the human brain against Alzheimer’s, and contribute to the clinical efficacy of ALZ-801 by inhibiting the formation of toxic soluble amyloid oligomers at therapeutic concentrations,” said John Hey, PhD, Chief Scientific Officer of Alzheon. “Our data support the central role of amyloid oligomers in the initiation of the pathogenic cascade of Alzheimer’s disease, as well as the potential preventive and therapeutic approaches that could be applied to counteract these neurotoxic oligomers. Based on the emerging scientific and clinical trial data from Alzheon, as well as independent studies which highlight amyloid oligomers as key drivers of Alzheimer’s, we have developed ALZ-801 as a pioneering small molecule, which directly blocks the formation of amyloid oligomers, and may slow or stop Alzheimer’s disease progression.”

About ALZ-801ALZ-801, a novel, oral anti-amyloid drug candidate is an optimized prodrug of tramiprosate that has shown promising results in analyses of Phase 3 clinical data. ALZ-801 received Fast Track designation by the U.S. Food and Drug Administration (FDA) in October 2017. The clinical data for ALZ-8013 and its active agent, tramiprosate, suggest long-term clinical efficacy in AD patients with the APOE4 genotype, along with a favorable safety profile.1,2 ALZ-801 acts through a novel molecular mechanism of action blocking the formation of toxic amyloid oligomers4 associated with the development and progression of AD. The initial Phase 3 program for ALZ-801 will focus on patients with the homozygous APOE4/4 genotype at the Mild stage of AD, with the potential for future expansion to additional Alzheimer’s populations.

About AlzheonAlzheon, Inc. is committed to developing innovative medicines by directly addressing the underlying pathology of devastating neurodegenerative disorders. Our lead Alzheimer’s clinical candidate, ALZ-801, is a Phase 3-ready, first-in-class, small molecule oral inhibitor of beta amyloid aggregation and neurotoxicity – hallmarks of Alzheimer’s disease. ALZ-801 is a novel prodrug that builds on the safety and efficacy profile of the active compound tramiprosate, which has been evaluated in clinical trials involving over 2,000 Alzheimer’s patients. Our clinical expertise and technology platform are focused on developing drug candidates using a Precision Medicine approach based on individual genetic and biological information to advance therapies with the greatest impact for patients.